Methods for the preparation and functionalization of indoles are important due to the frequent appearance of indoles in biologically interesting natural and unnatural compounds. Sundberg, R. J. Indoles; Academic Press: London, 1996; Saxton, J. E. Nat. Prod. Rep. 1997, 559; Borschberg, H.-J. Curr. Org. Chem. 2005, 9, 1465; Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th ed.; Thieme: New York, 2001; “Friedel-Crafts Alkylation”: Olah, G. A.; Krishnamurty, R.; Prakash, G. K. S. in Comprehensive Organic Synthesis, Vol. III (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1st ed., 1991, p. 293; Roberts, R. M. A.; Khalaf, A. Friedel-Crafts Alkylation Chemistry A Century of Discovery, Marcel Dekker, New York, 1984; Olah, G. A. Friedel-Crafts and Related Reactions, Vol. II, part 1, Wiley-Interscience, New York, 1964; and Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
The development of catalytic enantioselective methods for the facile synthesis of optically active indole derivatives has recently attracted significant attention. The electron-rich nature of the indole ring renders enantioselective Friedel-Crafts reactions of indoles with readily available prochiral electrophilic starting materials a strategically important approach to access enantiomerically enriched indole derivatives. For reviews, see: Jørgensen, K. A. Synthesis 2003, 1117; b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550. For recent examples of catalytic enatioselective synthesis of indole derivatives, see: a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424; b) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060; c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086; d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558. For catalytic asymmetric Michael additions of indoles catalyzed by chiral Lewis acids, see: a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2001, 40, 160; b) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030; c) Bandini, M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetrahedron Lett. 2003, 44, 5846; d) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780; e) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942; f) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154 g) Jia, Y.-X., Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75; h) Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739; for resolution of epoxides with indole see: i) Bandini, M.; Cozzi, P.; Melchiorre, G. P.; Umami-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 84. For catalytic asymmetric Michael additions of indoles catalyzed by organic catalyst, see: a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370; b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172; c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7824; d) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051; e) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566; f) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem. Int. Ed. 2005, 44, 6576. For catalytic asymmetric addition of indoles to ethyl 3,3,3-trifluoropyruvate, see: a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2001, 66, 1009; b) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M. S.; Mhadgut, C.; Yan, P.; Prakash, G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086. For catalytic asymmetric Friedel-Crafts additions of indoles to imines, see: Johannsen, M. Chem. Comm. 1999, 2233.
Several enantioselective conjugate additions of indoles to Michael acceptors have been developed using either chiral metallic or organic catalysts. These studies established considerable substrate scope with respect to both the indoles and the Michael acceptors. In contrast, a catalytic enantioselective 1,2-nucleophilic addition that is broadly applicable to both indoles and carbonyl compounds is lacking, although such a reaction would represent another direct and versatile means to synthesize enantiomerically enriched chiral indole derivatives. While high enantioselectivity has been achieved with both chiral metal and organic catalysts, these catalysts are only effective with ethyl 3,3,3-trifluoropyruvate as the electrophile.
In a recent report of the cinchonine- or cinchonidine-catalzyed addition of indoles to ethyl 3,3,3-trifluoropyruvate, Török, Prakash and coworkers demonstrated that blocking either the quinuclidine or the 9-OH led to dramatically reduced enantioselectivity with the natural cinchona alkaloids. Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M. S.; Mhadgut, C.; Yan, P.; Prakash, G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086. Thus, cinchonine was postulated to function as a base-acid bifunctional catalyst to activate simultaneously the indole and ethyl 3,3,3-trifluoropyruvate via the quinuclidine and the 9-OH moiety, respectively, to achieve synthetic useful enantioselectivity.
In addition, synthetic and mechanistic studies have established that cooperative hydrogen-bonding catalysis with 6′-OH cinchona alkaloids as base-acid bifunctional catalysts can provide a useful platform for the development of highly enantioselective conjugate additions and nitroaldol (Henry) reaction. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906-9907; Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. 2005, 44, 105-108; Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167-169; Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948-8949; Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732; and Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem. Int. Ed. 2006, 45, 947. While the high efficiency of 6′-OH cinchona alkaloids in the promotion of mechanistically unrelated C—C bond formations had been demonstrated, it was unknown if the 6′-OH cinchona alkaloids might function as efficient catalysts for enantioselective Friedel-Crafts reactions of indoles with carbonyl compounds. In particular, whether the more acidic 6′-phenol (relative to the C9-alcohol) could be used to achieve effective activation of a broad range of carbonyls for the enantioselective Friedel-Crafts reaction with indoles. Remarkably, we have discovered that cinchona alkaloids can be used to achieve effective activation of a broad range of carbonyls for the asymmetric Friedel-Crafts reaction.